Papaverine is an FDA-approved phosphodiesterase 10A (PDE10A) inhibitor and its clinical use is due to these effects on blood pressure and vascular tone. However, it was found to also be a potent inhibitor of mitochondrial complex I. Papaverine’s mitochondrial complex I inhibition has been shown to be responsible for increased tumor oxygenation and enhanced radiation response. But, when used in oncology, papaverine’s vascular effects can cause negative side-effects, especially in patients with cardiovascular co-morbidities.

The Need

In the field of radiation therapy, tumor hypoxia poses a significant challenge, dampening the efficacy of treatment and limiting the biologically effective dose. Hypoxic tumors are inherently resistant to treatment by radiotherapy. Investigators have known this for over 50 years, and yet there is not an efficient way to radiosensitize this subgroup of solid tumors. Hypoxia exists because of an inherent mismatch in the delivered oxygen versus the consumed oxygen within the tumor. Many groups have tried to deliver more oxygen to the tumor, but this has been ineffective clinically. Effective treatments that prepare the tumor cell to respond to radiotherapy are needed to improve patient outcomes.

The Technology

Researchers at The Ohio State University have developed novel compounds that harness the power of mitochondrial respiration modulation to elevate tumor oxygenation and amplify the tumor’s response to radiation therapy while removing the unwanted vascular effects of papaverine. These novel derivatives of papaverine provide for a breakthrough radiosensitizing strategy by offering improved effectiveness with potentially fewer side effects. The novel compounds have been designed to retain the mitochondrial C1 inhibiting activity while removing the PDE10A activity. Crucially, this strategy selectively enhances radiation response in tumor cells while sparing well-oxygenated normal tissue, elevating the therapeutic index of radiotherapy.

Benefits/Advantages

• Enhanced Radiation Response

• Fewer Side Effects

• Elevated Therapeutic Index

Multiple Patent Applications pending